2fhi

From Proteopedia

Revision as of 19:59, 12 November 2007

SUBSTRATE ANALOG (IB2) COMPLEX WITH THE HIS 96 ASN SUBSTITUTION OF THE FRAGILE HISTIDINE TRIAD PROTEIN, FHIT

Overview

Alterations in the FHIT gene at 3p14.2 occur as early and frequent events, in the development of several common human cancers. The ability of human, Fhit-negative cells to form tumors in nude mice is suppressed by stable, reexpression of Fhit protein. Fhit protein is a diadenosine, P1,P3-triphosphate (ApppA) hydrolase whose fungal and animal homologs form, a branch of the histidine triad (HIT) superfamily of nucleotide-binding, proteins. Because the His-96 --> Asn substitution of Fhit, which retards, ApppA hydrolase activity by seven orders of magnitude, did not block, tumor-suppressor activity in vivo, we determined whether this mutation, affected ApppA binding or particular steps in the ApppA catalytic cycle., Evidence is presented that His-96 --> Asn protein binds ApppA well and, forms an enzyme-AMP intermediate extremely poorly, suggesting that, Fhit-substrate complexes are the likely signaling form of the enzyme. The, cocrystal structure of Fhit bound to Ado-p-CH2-p-ps-Ado (IB2), a, nonhydrolyzable ApppA analog, was refined to 3.1 A, and the structure of, His-96 --> Asn Fhit with IB2 was refined to 2.6 A, revealing that two, ApppA molecules bind per Fhit dimer; identifying two additional, adenosine-binding sites on the dimer surface; and illustrating that His-98, is positioned to donate a hydrogen bond to the scissile bridging oxygen of, ApppA substrates. The form of Fhit bound to two ApppA substrates would, present to the cell a dramatically phosphorylated surface, prominently, displaying six phosphate groups and two adenosine moieties in place of a, deep cavity lined with histidines, arginines, and glutamines.

About this Structure

2FHI is a Single protein structure of sequence from Homo sapiens with IB2 as ligand. Active as Bis(5'-adenosyl)-triphosphatase, with EC number 3.6.1.29 Structure known Active Site: HIT. Full crystallographic information is available from OCA.

Reference

Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit., Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C, Proc Natl Acad Sci U S A. 1998 May 12;95(10):5484-9. PMID:9576908

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